Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which requires time to develop and is dependent on previous interaction with specific pathogens, the ability of PMNs to kill infectious microorganisms is immediate, non-specific, and not dependent on previous pathogen exposure. Inasmuch as PMNs produce toxic microbicidal components and are the predominant immune cell in most bacterial infections, moderation of infection-induced inflammation is critical for limiting host tissue destruction. Recent evidence suggests PMN apoptosis facilitates resolution of bacterial infections, an idea supported by the finding that pathogens alter neutrophil apoptosis to survive. A key aspect of our research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as apoptosis, processes crucial for the resolution phase of inflammation. These studies established a global model of host cell-pathogen interaction that provides fundamental insight into the resolution of infection in humans.[unreadable] [unreadable] A second focus of research in my laboratory investigates how bacterial pathogens such as Staphylococcus aureus cause human disease. Although most bacteria are killed readily by PMNs, certain strains of S. aureus have evolved mechanisms to circumvent destruction by neutrophils and thereby cause human infections. Notably, S. aureus is the most frequent etiologic agent causing bloodstream infection, skin and soft tissue infection, and lower respiratory tract infection in much of the world, including the United States. In addition, the pathogen has become increasingly resistant to antibiotics over the past few decades and methicillin-resistant S. aureus (MRSA) is a leading cause of hospital-acquired infections. Thus, treatment options are limited. Hospital-acquired MRSA infections are also typical of individuals with predisposing risk factors. In contrast, community-associated (or acquired) MRSA (CA-MRSA) cause disease in otherwise healthy individuals, and these infections can be severe/fatal. There has been an alarming increase in the number of CA-MRSA infections worldwide, which includes an ongoing epidemic of CA-MRSA in the United States. The molecular basis for the increased incidence and severity of CA-MRSA disease is not known. We hypothesize that the ability of bacteria to cause disease is largely due to pathogen-derived factors that alter normal neutrophil function and individual host susceptibility. Therefore, a better understanding of the bacteria-PMN interface at the cell and molecular levels will provide information critical to our understanding, treatment, and control of disease caused by bacterial pathogens. S. aureus is an ideal model pathogen with which to test our hypothesis because it is an important cause of human disease, it can be multi-drug resistant and thus hard to eradicate, and neutrophils are the first line of defense against S. aureus infections. To date, our studies include identification of genes and proteins used by CA-MRSA to evade destruction by human neutrophils, hence contributing to virulence, survival and pathogenesis.